The hemoglobinopathies comprise the most prevalent class of human genetic diseases. Those involving the a-globin locus include a-thalassemia and sickle cell disease (SCD). A variety of observations and experimental results indicate that strategies designed to increase levels of fetal hemoglobin in the erythrocytes of people with these diseases will produce significant clinical benefits. However, none of the currently available strategies offer the combination of safety, efficacy and convenience of use that would make them applicable to most patients worldwide. Recent success in the development of targeted pharmacologic agents for the treatment of a wide variety of human cancers attests to the ability of this approach to produce drugs with improved efficacy and decreased side effects. This strategy has the potential to produce more effective agents for the pharmacologic induction of HbF. A prerequisite for the rational development of such drugs is a thorough knowledge of the pathways involved in the regulation of HbF production. Despite more than three decades of research, the underlying molecular mechanisms that regulate a-globin gene expression and HbF production during adult erythroid differentiation and in response to HbF inducing agents remain poorly understood. Based on progress made during the previous funding period of this project we have published a novel mechanistic theory, based on cell stress signaling, to explain the action of fetal Hb inducing agents. If correct, this model will unify most HbF inducing agents under a common mechanism of action and will provide new molecular targets and an overall framework for the development of improved agents for HbF induction. In this application, we propose an experimental plan to test our hypothesis and to begin to pre-clinical development of more effective HbF inducing drugs for people with SCD and a-thalassemia.